The incidence of melanoma has been increasing for the past several years. In the United States, more than 60,000 patients are estimated to be diagnosed with melanoma with approximately 8,000 deaths in 2006. The overall lifetime risk of developing melanoma is 1 in 77 for women and 1 in 52 for men.
Melanomas vary greatly in aggressiveness. Very aggressive melanomas grow rapidly, metastasize early, and progress quickly, while less aggressive melanomas grow with a more indolent course. Consequently, much effort has gone into defining the characteristics of the more aggressive melanoma phenotype in hopes of designing therapies that target these more aggressive tumors and sparing patients with less aggressive melanomas often toxic adjuvant therapy designed to lessen the likelihood of recurrence and metastasis.
Metastasis is a multistep process requiring a melanoma cell to escape the control of the local microenvironment and invade the basement membrane. Once in contact with the interstitial microenvironment, integrins on the melanoma cell surface bind to the extracellular matrix (ECM) and this initiates signal transduction events that promote cell survival, migration, and invasion. One signal transduction pathway that appears to be important in melanoma progression is the mitogen activated protein kinase (MAPK) pathway. This signaling pathway begins with Ras activation and proceeds through the activation of Raf and MEK 1/2, resulting in the activation of ERK 1/2. The MAPK pathway controls processes central to melanoma progression, including cell growth, apoptosis, and cell migration. For instance, activation of this pathway leads to upregulation of the expression of proteases such as urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMP), and tissue plasminagen activator (tPA) that break down the surrounding collagen matrix and promote cell invasion and migration.
Phenotypically aggressive melanoma cells are also very plastic, able to mimic the activities of endothelial cells and to participate in processes such as neovascularization and the formation of fluid-conducting, matrix-rich meshworks. This vasculogenic mimicry has been shown to be a common characteristic of aggressive melanomas and appears to be controlled by complex signal transduction networks within the cell. Indeed, one of the main signaling cascades involved in vasculogenic mimicry is the MAPK pathway, and blocking the phosphorylation of ERK1/2 results in an inhibition of vasculogenic mimicry in three dimensional collagen cultures.
With increased knowledge of the genetic alterations that lead to a more aggressive melanoma phenotype, investigators have been searching for strategies designed to interrupt the relevant signaling pathways and result in either the inhibition of melanoma progression or the preferential killing of melanoma cells. However, different genetic alterations can lead to the activation of the same cellular pathways and inhibiting one pathway component, such as Raf, may not be an effective strategy if other genetic alterations result in downstream target activation. Consequently, we need to continue to work out the relevant signal transduction networks to be able to develop therapies to treat patients with melanoma.